2013 Grants - Chang

Functional Protein Interactions in Alzheimer's Disease and Down Syndrome

Down Syndrome/Alzheimer's Disease Investigator-Initiated Program

People with Down syndrome have a high risk of developing Alzheimer's disease, often experiencing Alzheimer's-related brain changes by age 40. Yet a significant number of individuals with Down syndrome do not develop dementia. Researchers are now studying the molecular mechanisms that may protect people with Down syndrome from acquiring Alzheimer's. One such mechanism involves the protein Down syndrome critical region 1 (DSCR1). The gene for DSCR1 is located on the same chromosome (or organized segment of genetic material) as the gene for amyloid precursor protein (APP). In Down syndrome there is an extra copy of chromosome 21, giving three copies of the DSCR1 and APP genes. Both of these proteins become abnormally produced in Down syndrome. Overproduction of APP has been shown to promote the creation of toxic beta-amyloid, an APP fragment that is a key suspect in Alzheimer's disease. Yet it is unclear whether abnormal DSCR1 production stimulates or hinders Alzheimer's development.

In preliminary research, Karen T. Chang, Ph.D., and colleagues studied the effects of a DSCR1-like protein (called nebula) in fruit flies engineered to develop high levels of APP. They found that by increasing brain production of nebula in their animals, they could reduce levels of amyloid-related brain cell dysfunction and death. These findings suggest DSCR1 may protect people with Down syndrome from the brain cell damage characteristic of Alzheimer's.

For their current grant, Dr. Chang and colleagues hope to verify their earlier results with fruit flies. They also hope to clarify the exact mechanisms underlying nebula's protective effects. Specifically, the researchers will assess whether increased nebula production helps protect the functions of axons—the arm-like extensions used to communicate between nerve cells. Axonal dysfunction hinders the ability of neurons to communicate with one another and can lead to memory deficits. The investigators will also conduct similar experiments with cultured mouse neurons to further validate their findings. Ultimately, Dr. Chang's study could shed new light on the molecular links between Down syndrome and Alzheimer's disease. It could also point toward novel therapies for both disorders.